Highlights from Recent Cancer Literature
Journal: Cancer Research (2018)

Oncogenic activation of ERG through TMPRSS2-ERG fusion is a recurrent driver alteration in tumorigenesis, evident in the preinvasive stages of prostate cancer (CaP). Mohamed and colleagues screened small-molecule libraries for inhibitors of ERG protein in TMPRSS2-ERG harboring VCaP prostate cancer cells using an in-cell Western assay. They identified ERGi-USU, a small molecule that selectively inhibited growth of ERG-positive cancer cell lines in vitro and VCaP tumor xenografts in vivo, with no apparent toxicity. A combination of ERGi-USU with enzalutamide, a nonsteroidal antiandrogen, showed additive effects in inhibiting growth of VCaP cells. Additionally, ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced a ribosomal stress signature.Expert Commentary: This study identifies and characterizes a small molecule that is a highly selective inhibitor of growth of ERG-positive cancer cells in vitro and in vivo. The observed selectivity of ERGi-USU for only ERG-positive cancer cells offers a unique opportunity to develop further ERG-targeted therapeutic strategies.Mohamed AA, Xavier CP, Sukumar G, Tan SH, Ravindranath L, Seraj N, et al. Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth. Cancer Research; Published first April 30, 2018; doi: 10.1158/0008-5472.CAN-17-2949.The process of epithelial-to-mesenchymal transition (EMT), whereby cells lose their epithelial characteristics and acquire a mesenchymal phenotype, is associated with tumor stemness, metastatic potential, and resistance to therapy. Using animal models of skin and mammary cancer that undergo EMT spontaneously, Pastushenko and colleagues identified multiple, functionally independent, EMT tumor subpopulations exhibiting differences in plasticity, invasiveness, and metastatic potential. Molecular characterization revealed distinct genetic and epigenetic regulatory pathways controlling the EMT transition states. In addition, localized tumor microenvironments and, in particular, immune infiltration and expression of cytokines directly contributed to the different tumor transition states and their spatial organization.Expert Commentary: Understanding the different tumor transition states and how they are regulated by the microenvironment provide opportunities to develop strategies to target tumor heterogeneity and to provide more effective therapies.Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, et al. Identification of the tumour transition states occurring during EMT. Nature 2018;556:463–8.Pushalkar and colleagues demonstrate a cancer-promoting role of the microbiome in pancreatic ductal adenocarcinoma (PDAC). The composition of gut bacteria, in comparison to healthy groups, is different in patients with PDAC and in autochthonous mouse models of PDAC. Moreover, gut bacteria can translocate to the pancreas. In cancerous pancreata, translocation is more prevalent and selective for specific phyla. Progression of PDAC is delayed in germ-free or antibiotic-treated mice. In the presence of a microbiome, macrophages had lower levels of stimulatory molecules (CD86 and MHC-II), which reduced their capacity to stimulate T-cell responses. Mechanistically, bacteria instructed the programming of immunosuppressive macrophages via engagement of Toll-like receptors associated with bacterial detection (TRL2/4/5). In stark contrast to other cancers, checkpoint blockade immunotherapy with anti-PD1 was blunted in the presence of the PDAC microbiome.Expert Commentary: In contrast to a prevailing paradigm in cancer, in PDAC, coupling checkpoint blockade immunotherapy with antibiotic treatment may be efficacious.Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 2018;8:403–16.The interaction between the seed (tumor) and soil (stroma) is critical for tumorigenesis. Yan and colleagues describe a novel MYC-miR-105-MYC activation loop that metabolically reprograms cancer-associated fibroblasts (CAF). Exosomes from high MYC-expressing breast cancer cells induced MYC signaling, and glucose and glutamine metabolism in CAFs. This was mediated through exosomal miR-105, which decreased expression of MXI1 that suppresses transcription from the MYC promoter, resulting in increased MYC expression. These CAFs utilized glycolysis and glutaminolysis to survive single nutrient depletion in a miR-105-MYC–dependent manner. Reprogramed CAFs could also detoxify lactic acid and ammonium through converting them to key metabolic nutrients. Activity of this pathway was observed in high MYC-expressing patient tumors and CAFs.Expert Commentary: The MYC-miR-105-MYC pathway is critical for metabolic stability in the tumor microenvironment. An understanding of these key tumor-stroma interactions may lead to a novel therapeutic target in breast cancer.Yan W, Wu X, Zhou W, Fong MY, Cao M, Liu J, et al. Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 2018;20:597–609.Isocitrate dehydrogenase 1 (IDH1) mutations in glioma drive high levels of the oncometabolite 2-hydroxyglutarate (2HG). To evaluate pharmacodynamics within a clinical trial of the IDH1 inhibitor IDH305, Andronesi and colleagues monitored intratumoral levels of 2HG in IDH1 mutant tumors using magnetic resonance spectroscopy. After a week of treatment with IDH305, significant reductions in 2HG were observed with no change in other metabolites or in tumor size. Increases in lactate and glutamine/glutamate were also observed after IDH1 inhibition, suggesting metabolic reprogramming through inhibition of lactate dehydrogenase and increased levels of NADPH. Finally, the authors correlated metabolic profile with cellular density by comparing the changes in apparent diffusion coefficient (an indicator of cell density) with the changes in 2HG.Expert Commentary: This study provides proof of principle that in vivo “radiopharmacodynamics” can monitor in vivo drug activity and targeted treatment response in malignant brain tumors.Andronesi OC, Arrillaga-Romany IC, Ly KI, Bogner W, Ratai EM, Reitz K, et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate. Nature Commun 2018;9:1474. DOI: 10.1038/s41467-018-03905-6.Transcriptional dysregulation of the MYC oncogene is frequent in aggressive cancers, often due to gain of a super-enhancer within a 2.8 Mb topological-associated domain (TAD), where MYC resides. Schuijers and colleagues show that a wide variety of cancer-specific super-enhancers loop to the MYC gene via a conserved CTCF binding site located 2 kb upstream of the MYC promoter. Mutation of the enhancer-docking site in cancer cells reduced binding of CTCF, expression of MYC, and proliferation. Hypermethylation of this enhancer-docking site blocked, whereas hypomethylation enabled CTCF-binding. The authors found similar enhancer-docking sites at additional genes, many of which play important roles in cancers, suggesting a common mechanism by which oncogenes can hijack enhancers and that enables a target gene to be regulated by different enhancer elements in different cell types.Expert Commentary: Together, these data suggest that an MYC enhancer-docking site is a common vulnerability in diverse cancer cells.Schuijers J, Manteiga JC, Weintraub AS, Day DS, Zamudio AV, Hnisz D, et al. Transcriptional dysregulation of MYC reveals common enhancer-docking mechanism. Cell Rep 2018;23:349–60.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.